Percutaneous coronary intervention versus coronary artery bypass grafting for adults with diabetes and multivessel coronary disease

  • Protocol
  • Intervention

Authors


Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

To assess the effects of PCI versus CABG for adults with diabetes and MCD.

Background

Description of the condition

Diabetes mellitus (DM) is a metabolic disorder resulting from a defect in insulin secretion, insulin action, or both. Long-term hyperglycemia induces damage in both microcirculation and major arterial vessels resulting in damage to multiple organs (ADA 2013). Coronary arteries are also affected, and people with diabetes are more susceptible to develop coronary artery disease (CAD) than non-diabetic individuals (Haffner 1998; Lee 2004; Sprafka 1991). People with DM and CAD have worse prognosis than nondiabetic individuals (Hammoud 2000; Sprafka 1991). For instance, CAD is the cause of 68% of deaths in people with diabetes in the United States (Bonow 2004; CDC 2011).

Approximately 25% of individuals with from multivessel coronary disease (MCD) have DM as a comorbidity. MCD consists of a reduction of at least 50% of the transverse area of two or more major coronary arteries (Smith 2002), and constitutes a therapeutically challenging clinical entity. Treatment options include either open chest surgery with coronary artery bypass grafting (CABG), or the minimally invasive therapy, percutaneous coronary intervention (PCI), which includes percutaneous transluminal coronary angioplasty (PTCA) with stenting.

Description of the intervention

PCI is an intravascular intervention that reopens occluded coronary arteries. This procedure involves angioplasty and the placement of a bare metal or drug-eluting stent in the affected vessels. Currently, PCI constitutes the preferred technique in 75% of the cases where revascularization therapy is necessary (Epstein 2011).

The alternative to PCI is CABG, which is a major cardiac surgery that, by using either internal mammary artery or reversed saphenous veins harvested from the legs, connects the segment of the coronary artery distal to the severely stenotic or occluded area with the normal arterial circulation, thereby reestablishing blood flow in the ischemic area (Hillis 2011).

Adverse effects of the intervention

The main adverse effects from CABG surgery are death, nonfatal myocardial infarction, nonfatal stroke, gastrointestinal bleeding, acute renal failure, short-term cognitive changes, perioperative bleeding and infections that include mediastinitis and deep sternal wound infection, perioperative myocardial dysfunction and arrhythmias.

The main complications from PCI are death, nonfatal myocardial infarction, urgent unplanned revascularization, arterial dissection or perforation, pericardial tamponade, stent restenosis and thrombosis, nonfatal stroke, contrast-induced nephropathy and hemorrhage.

How the intervention might work

The ischemia of the cardiac tissue distal to an occluded or significantly stenotic artery is the pathophysiological basis of the CAD. The revascularization therapy with either PCI or CABG intends to reestablish coronary blood flow.

Why it is important to do this review

CABG and PCI have shown similar results in important outcomes such as myocardial infarction rate, mortality, and improvement of angina post intervention. However, the requirement of a second reperfusion intervention has been shown to be lower with CABG than with PCI therapy (Henderson 1998). According to the Society of Thoracic Surgeons, DM increases the mortality and morbidity from CABG (Shahian 2009). Having in mind these aspects regarding the advantages and disadvantages of CABG and PCI therapies, plus that the initial cost of CABG is much higher than that for PCI therapy (Magnuson 2013), choosing for the right reperfusion method in a person with MCD and DM is not always easy.

From the publication of the 'Bypass Angioplasty Revascularization Investigation' (BARI) in 1995, there are supportive data that people with diabetes with MCD present higher survival with CABG than with PCI (Ferguson 1995). Since 1995, PCI and CABG techniques have improved substantially; therefore, the results from the BARI study are difficult to generalize to present clinical practice. One more recent clinical trial, 'Future REvascularization Evaluation in patients with Diabetes mellitus: Optimal management of Multivessel disease' (FREEDOM), has been published (Farkouh 2012). The results of this clinical trial are supportive of the data shown in the BARI study. Moreover, one post hoc analysis of the FREEDOM clinical trial has shown a cost-effective advantage with CABG over PCI therapy (Magnuson 2013).

The subgroup of people with DM and MCD is an important public health concern because of the associated prevalence, mortality, morbidity, and medical costs. PCI and CABG are very different therapies and both aim at revascularize the ischemic cardiac tissue.

Although some systematic reviews have addressed the question of whether CABG or PCI is superior in the treatment of MCD in people with diabetes (Hakeem 2013; Zhang 2012), they did not consider important outcomes such as adverse events, health-related quality of life, and socioeconomic effects. In addition, important data have become evident since their publication. Therefore, this systematic review will provide a more updated analysis and more complete information, since we will investigate a larger number of outcomes. Hence, this review will provide helpful information for decision makers in public health.

Objectives

To assess the effects of PCI versus CABG for adults with diabetes and MCD.

Methods

Criteria for considering studies for this review

Types of studies

We will include randomized controlled clinical trials (RCTc).

Types of participants

We will include studies evaluating adults (older than18 years) with diabetes affected by MCD requiring PCI or CABG.

Diagnostic criteria
  1. DM: to be consistent with changes in classification and diagnostic criteria of DM over the years, the diagnosis should be established using the standard criteria valid at the time of the trial commencing (e.g. American Diabetes Association (ADA 1999; ADA 2008); World Health Organization (WHO 1998)). Ideally, diagnostic criteria should have been described. If necessary, we will use the study authors' definition of DM. We plan to subject diagnostic criteria to a sensitivity analysis.

  2. MCD will be defined as the identification of two or more main epicardial vessels (left anterior descending, left circumflex, or right coronary artery) (Kirschbaum 2010).

Types of interventions

Intervention

PCI (with or without stent).

Comparator

CABG (any variant of the technique).

We will not include studies comparing PCI or CABG versus medical treatment, no treatment, or other treatments. Concomitant interventions will have to be similar in the intervention and comparator groups to establish fair comparisons.

Types of outcome measures

Primary outcomes
  • All-cause mortality.

  • Adverse events.

Secondary outcomes
  • Stroke.

  • Nonfatal myocardial infarction.

  • Symptomatic angina.

  • Repeated revascularization.

  • Health-related quality of life.

  • Metabolic control.

  • Socioeconomic effects.

Method and timing of outcome measurement
  • All-cause mortality: defined as death from any cause and measured at 30 days, and one, two, three, four, and five years after the intervention.

  • Adverse events: apart from hypoglycemic episodes, defined as acute renal failure, perioperative bleeding and infections, stent restenosis, and thrombosis. Measured within the first 30 days and at one year after the intervention.

  • Stroke: as defined by the study author and measured within the first 30 days after the procedure, at intermedium follow-up (one to three years), and at late follow-up (four to five years).

  • Nonfatal myocardial infarction: as defined by the study author and measured within the first 30 days after the procedure, at intermedium follow-up (one to three years, and at late follow-up (four to five years).

  • Symptomatic angina: measured using the Seattle Angina Questionnaire (SAQ) at one month, six months, and one year.

  • Repeated revascularization: defined as need of revascularization and measured within five years after the initial procedure.

  • Health-related quality of life: measured with the SAQ or 36-item Short Form (SF-36) at one month, six months, and one year.

  • Metabolic control: defined as analysis of glycosylated hemoglobin A1c (HbA1c) measured at one year after the procedure.

  • Socioeconomic effects: defined as cumulative five-year costs, life-years, quality-adjusted life-year (QALY), hospitalization length, and time out of work. Measured within five years after the procedure.

'Summary of findings' table

We will present a 'Summary of findings' table reporting the following critical (for decision-making) outcomes.

  1. All-cause mortality.

  2. Stroke.

  3. Nonfatal myocardial infarction.

  4. Repeated revascularization.

  5. Adverse events.

  6. Health-related quality of life.

  7. Socioeconomic effects.

Search methods for identification of studies

Electronic searches

We will search the following sources from inception to the present.

  • The Cochrane Library.

  • MEDLINE.

  • EMBASE.

We will also search the following trial registers.

For detailed search strategies, see Appendix 1. We will continuously apply PubMed's 'My NCBI' (National Center for Biotechnology Information) email alert service for identification of newly published studies using a basic search strategy (see Appendix 1). Four weeks before we submit the final review draft to the Cochrane Metabolic and Endocrine Disorders Group (CMED) for editorial approval, we will perform a complete update search on all specified databases. Should we detect new studies for inclusion, we will evaluate these and incorporate findings in our review before submission of the final review draft.

If we detect additional relevant key words during any of the electronic or other searches, we will modify the electronic search strategies to incorporate these terms and document the changes. We will place no restrictions on the language of publication when searching the electronic databases or reviewing reference lists in identified studies.

Searching other resources

In order to identify articles potentially missed through the electronic searches, grey literature and unpublished studies, we will:

  1. handsearch reference lists of all included studies and of relevant reviews retrieved by electronic searching to identify other potentially eligible trials or ancillary publications. We will conduct a search for other systematic reviews and health technology assessment reports in the CRD Database (www.crd.york.ac.uk/crdweb) and Epistemonikos (www.epistemonikos.org). The list of reviews and health technology assessment reports screened will be reported as an appendix.

  2. handsearch conference proceedings for the last five years from the following events: World Congress of Cardiology, European Society of Cardiology (ESC) Congress, and American College of Cardiology (ACC) Annual Scientific Sessions.

  3. contact corresponding authors of included studies, local and foreign experts in the field, and pharmaceutical companies representatives that market coronary stents (e.g. Boston Scientific Corporation, Medtronic, Inc., Abbott Laboratories) for any additional published or unpublished data.

  4. run a Scholar Google search for key terms and authors.

Data collection and analysis

Selection of studies

To determine the studies to be assessed further, two review authors (CB, CR) will independently scan the abstract, title, or both sections of every record retrieved by the searches. We will investigate all potentially eligible articles as full text. We will resolve any discrepancies through consensus or recourse to a third review author (GR). We will use the software EROS (www.eros-systematic-review.org) to manage screening, assessment of full-text articles, and resolution of discrepancies.

We will present an adapted PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow-chart of study selection (Figure 1) (Liberati 2009).

Figure 1.

Study flow diagram.

Data extraction and management

For studies that fulfil inclusion criteria, two review authors (CB, CR) will independently extract data about relevant population and intervention characteristics using data extraction sheets entered in EROS and standard data extraction templates with any disagreements to be resolved by discussion, or, if required, by consultation with a third review author (GR) (for details see (for details see Table 1; Appendix 2; Appendix 3; Appendix 4; Appendix 5; Appendix 6; Appendix 7; Appendix 8; Appendix 9; Appendix 10; Appendix 11; Appendix 12; Appendix 13).

Table 1. Overview of study populations
  1. aAccording to power calculation in study publication or report

    bDuration of intervention or follow-up, or both, under randomized conditions until end of study

    "-" denotes not reported

    CABG: coronary artery bypass grafting; ITT: intention-to-treat; N/A: not applicable; PCI: percutaneous coronary intervention

CharacteristicIntervention(s) and comparator(s)Sample sizeaScreened/eligible
[N]
Randomized
[N]
Safety
[N]
ITT
[N]
Analyzed
[N]
Finishing study
[N]
Randomized finishing study
[%]
Follow-up timeb
(1) Study IDCABG         
PCI         
  total:       
           
Grand total All CABG interventions    ...     ...   
  All PCI c omparators    ...     ...   
  All interventions and c omparators    ...     ...   

We will provide information including trial identifier about potentially relevant ongoing studies in the table 'Characteristics of ongoing studies' and in the appendix 'Matrix of study endpoints (trial documents)'. We will try to find the protocol of each included study, either in databases of trial registers or in publications of study designs, or both, and specify the data in the appendix 'Matrix of study endpoints (trial documents)'.

We will e-mail all authors of included studies to enquire whether they are willing to answer questions regarding their trials. We will present the results of this survey in Appendix 14. Thereafter, we will seek relevant missing information on the trial from the primary author(s) of the article, if required.

Furthermore, we will seek key unpublished information that is missing from reports of included studies.

Dealing with duplicate and companion publications

In the event of duplicate publications, companion documents or multiple reports of a primary study, we will maximize yield of information by collating all available data and use the most complete dataset aggregated across all known publications. In case of doubt, the publication reporting the longest follow-up associated with our primary or secondary outcomes will obtain priority.

Assessment of risk of bias in included studies

Two review authors (CB, CR) will assess the risk of bias of each included study independently. We will resolve disagreements by consensus, or by consultation with a third review author (GR).

We will assess risk of bias using The Cochrane Collaboration's tool for assessment of risk of bias (Higgins 2011a; Higgins 2011b). We will assess the following criteria in this assessment.

  • Random sequence generation (selection bias).

  • Allocation concealment (selection bias).

  • Blinding, separated for blinding of participants and personnel (performance bias) and blinding of outcome assessment (detection bias). Considering performance bias is almost impossible to avoid in the case of our intervention and comparison, we will evaluate if authors have taken any specific measure to address performance bias, including a detailed description of co-interventions.

  • Incomplete outcome data (attrition bias).

  • Selective reporting (reporting bias).

  • Other bias.

We will assess outcome reporting bias by integrating the results of 'Examination of outcome reporting bias' (Appendix 7), 'Matrix of study endpoints (trial documents)' (Appendix 6), and section 'Outcomes (outcomes reported in abstract of publication)' of the 'Characteristics of included studies' section (Kirkham 2010). This analysis will form the basis for the judgment of selective reporting (reporting bias).

We will judge 'Risk of bias' criteria as 'low risk', 'high risk', or 'unclear risk' and evaluate individual bias items as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a). We will present a 'Risk of bias' graph and a 'Risk of bias' summary figure.

We will assess the impact of individual bias domains on study results at endpoint and study levels.

For blinding of participants and personnel (performance bias), detection bias (blinding of outcome assessors), and attrition bias (incomplete outcome data), we intend to evaluate risk of bias separately for subjective and objective outcomes (Hróbjartsson 2013). We will consider the implications of missing outcome data from individual participants.

We will define the following endpoints as subjective outcomes.

  • Adverse events other than major bleeding and renal failure.

  • Any measure of severity of angina.

  • Revascularization need.

  • Health-related quality of life.

We will define the following outcomes as objective outcomes.

  • All-cause mortality.

  • Stroke.

  • Nonfatal myocardial infarction.

  • Functional capacity measured by any method that is not operator-dependent, such as oxygen consumption, walking test.

  • Major bleeding.

  • Renal failure.

  • Heart failure defined by echocardiographic assessment.

  • Binary restenosis rate.

  • Metabolic control (HbA1c).

  • Socioeconomic effects.

Measures of treatment effect

We will express dichotomous data as risk ratios (RRs) with 95% confidence intervals (CIs). We will express continuous data as mean differences (MD) with 95% CI or standardized mean differences (SMDs) when measured in different scales.

Unit of analysis issues

We will take into account the level at which randomization occurred, such as multiple observations for the same outcome. Considering the nature of the intervention, it is unlikely that we will find cross-over trials or cluster randomized trials. If these are found, we will take unit of analysis into account.

Dealing with missing data

We will obtain relevant missing data from study authors, if feasible, and evaluate important numerical data such as screened, eligible, randomized participants as well as intention-to-treat (ITT), as-treated, and per-protocol (PP) populations. We will investigate attrition rates, for example drop-outs, losses to follow-up, and withdrawals, and critically appraise issues of missing data and imputation methods (e.g. last observation carried forward (LOCF)).

Where standard deviations for outcomes are not reported we will impute these values by assuming the standard deviation of the missing outcome to be the mean of the standard deviations from those studies where this information was reported. We will investigate the impact of imputation on meta-analyses by means of sensitivity analysis.

Assessment of heterogeneity

In the event of substantial clinical, methodological, or statistical heterogeneity, we will not report study results as meta-analytically pooled effect estimates.

We will identify heterogeneity by visual inspection of the forest plots and by using a standard Chi2 test with a significance level of α = 0.1, in view of the low power of this test. We will examine heterogeneity using the I2 statistic, which quantifies inconsistency across studies to assess the impact of heterogeneity on the meta-analysis (Higgins 2002; Higgins 2003), where an I2 statistic of 75% or more indicates a considerable level of inconsistency (Higgins 2011a).

When we find heterogeneity, we will attempt to determine potential reasons for it by examining individual study and subgroup characteristics.

We expect the following characteristics to introduce clinical heterogeneity.

  • Coronary acute syndrome versus chronic angina.

  • Number of vessels involved.

  • Medicated versus nonmedicated stents.

  • Strict versus nonstrict treatment of DM.

Assessment of reporting biases

If we include 10 studies or more that investigate a particular outcome, we will use funnel plots to assess small study effects. Owing to several possible explanations for funnel plot asymmetry, we will interpret results carefully (Sterne 2011).

Data synthesis

Unless there is good evidence for homogeneous effects across studies, we will primarily summarize low risk of bias data using a random-effects model (Wood 2008). We will interpret random-effects meta-analyses with due consideration of the whole distribution of effects, ideally by presenting a prediction interval (Higgins 2009). A prediction interval specifies a predicted range for the true treatment effect in an individual study (Riley 2011). In addition, we will perform statistical analyses according to the statistical guidelines contained in the latest version of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a).

Subgroup analysis and investigation of heterogeneity

We will carry out the following subgroup analyses and plan to investigate interaction.

  • Medicated versus nonmedicated stents.

  • Gender.

  • Strict versus nonstrict medical treatment of DM.

Sensitivity analysis

We will perform sensitivity analyses in order to explore the influence of the following factors on effect sizes.

  • Restricting the analysis to published studies.

  • Restricting the analysis by taking into account risk of bias, as specified in the section, Assessment of risk of bias in included studies.

  • Restricting the analysis to very long or large studies to establish the extent to which they dominate the results.

  • Restricting the analysis to studies using the following filters: diagnostic criteria, imputation, language of publication, source of funding (industry versus other), country.

We will also test the robustness of the results by repeating the analysis using different measures of effect size (RR, odds ratio (OR), etc.) and different statistical models (fixed-effect and random-effects models).

Appendices

Appendix 1. Search strategies

Search terms and databases

Unless otherwise stated, search terms are free-text terms.

Abbreviations:

'$': stands for any character; '?': substitutes one or no character; adj: adjacent (i.e. number of words within range of search term); exp: exploded MeSH; MeSH: medical subject heading (MEDLINE medical index term); pt: publication type; sh: MeSH; tw: text word.

The Cochrane Library
#1 MeSH descriptor Angioplasty, Balloon, coronary explode all trees
#2 MeSH descriptor Percutaneous coronary intervention explode all trees
#3 (balloon in All Text and angioplast* in All Text)
#4 ((percutaneous in All Text near/6 coronary in All Text) and intervention* in All Text)
#5 PCI in All Text
#6 (implantation* in All Text and of in All Text and stent* in All Text)
#7 ((intervention* in All Text near/6 percutaneous in All Text) and coronary in All Text)
#8 ((revascularization* in All Text near/6 percutaneous in All Text) and coronary in All Text)
#9 (angioplast* in All Text near/6 coronary in All Text)
#10 (percutaneous in All Text and coronary in All Text)
#11 ((transluminal in All Text near/6 coronary in All Text) or (trans-luminal in All Text near/6 coronary in All Text))
#12 (#1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11)
#13 MeSH descriptor Coronary artery bypass explode all trees
#14 ((coronary in All Text and (bypass in All Text near/6 surger* in All Text)) or (coronary in All Text and (bypass in All Text near/6 graft* in All Text)))
#15 (aorto in All Text and (coronary in All Text near/6 bypass in All Text))
#16 (coronary in All Text and (artery in All Text near/6 bypass in All Text))
#17 (CABG in All Text or CAB in All Text or ACB in All Text)
#18 (coronary in All Text and artery in All Text and (bypass in All Text near/6 graft* in All Text))
#19 ((coronary in All Text near/6 bypass in All Text) and surg* in All Text)
#20 (#13 or #14 or #15 or #16 or #17 or #18 or #19)
#21 MeSH descriptor Diabetes mellitus explode all trees
#22 diabet* in All Text
#23 (IDDM in All Text or NIDDM in All Text or MODY in All Text or T1DM in All Text or T2DM in All Text or T1D in All Text or T2D in All Text)
#24 ((non in All Text and insulin* in All Text and depend* in All Text) or (noninsulin* in All Text and depend* in All Text) or (non in All Text and insulindepend* in All Text) or noninsulindepend* in All Text)
#25 ((insulin* in All Text and depend* in All Text) or insulindepend* in All Text)
#26 (#21 or #22 or #23 or #24 or #25)
#27 MeSH descriptor diabetes insipidus explode all trees
#28 (diabet* in All Text and insipidus in All Text)
#29 (#27 or #28)
#30 (#26 and not #29)
#31 (#12 and #20 and #30)
MEDLINE
1 exp Angioplasty, Balloon, Coronary/ or exp Percutaneous Coronary Intervention/
2 balloon angioplast*.tw,ot.
3 (percutaneous adj6 coronary intervention*).tw,ot.
4 PCI.tw,ot.
5 implantation* of stent*.tw,ot.
6 (intervention* adj6 percutaneous coronary).tw,ot.
7 (revascularization* adj6 percutaneous coronary).tw,ot.
8 (angioplast* adj6 coronary).tw,ot.
9 percutaneous coronary.tw,ot.
10 ((transluminal or trans-luminal) adj6 coronary).tw,ot.
11 or/1-10
12 exp Coronary Artery Bypass/
13 (coronary bypass adj6 surger*).tw,ot.
14 (coronary bypass adj6 graft*).tw,ot.
15 (aorto coronary adj6 bypass).tw,ot.
16 (coronary artery adj6 bypass).tw,ot.
17 (CABG or CAB or ACB).tw,ot.
18 (coronary artery bypass adj6 graft*).tw,ot.
19 (coronary adj6 bypass surg*).tw,ot.
20 or/12-19
21 exp Diabetes Mellitus/
22 diabet$.tw,ot.
23 (IDDM or NIDDM or MODY or T1DM or T2DM or T1D or T2D).tw,ot.
24 (non insulin$ depend$ or noninsulin$ depend$ or non insulin?depend$ or noninsulin?depend$).tw,ot.
25 (insulin$ depend$ or insulin?depend$).tw,ot.
26 exp Diabetes Insipidus/
27 diabet$ insipidus.tw,ot.
28 or/21-25
29 26 or 27
30 28 not 29
31 11 and 20 and 30
32 randomized controlled trial.pt.
33 controlled clinical trial.pt.
34 randomi?ed.ab.
35 placebo.ab.
36 drug therapy.fs.
37 randomly.ab.
38 trial.ab.
39 groups.ab.
40 or/32-39
41 Meta-analysis.pt.
42 exp Technology Assessment, Biomedical/
43 exp Meta-analysis/
44 exp Meta-analysis as topic/
45 hta.tw,ot.
46 (health technology adj6 assessment$).tw,ot.
47 (meta analy$ or metaanaly$ or meta?analy$).tw,ot.
48 (search* adj10 (medical databas*or medline or pubmed or embase or cochrane or cinahl or psycinfo or psyclit or healthstar or biosis or current content*)).tw,ot.
49 (systematic adj3 review*).tw,ot.
50 or/41-49
51 40 or 50
52 (comment or editorial or historical-article).pt.
53 51 not 52
54 31 and 53
55 limit 54 to humans
EMBASE
1 exp percutaneous coronary intervention/
2 balloon angioplast*.tw,ot.
3 (percutaneous adj6 coronary intervention*).tw,ot.
4 PCI.tw,ot.
5 implantation* of stent*.tw,ot.
6 (intervention* adj6 percutaneous coronary).tw,ot.
7 (revasculari?ation* adj6 percutaneous coronary).tw,ot.
8 (angioplast* adj6 coronary).tw,ot.
9 percutaneous coronary.tw,ot.
10 ((transluminal or trans-luminal) adj6 coronary).tw,ot.
11 or/1-10
12 exp coronary artery bypass graft/
13 (coronary bypass adj6 surger*).tw,ot.
14 (coronary bypass adj6 graft*).tw,ot.
15 (aorto coronary adj6 bypass).tw,ot.
16 (coronary artery adj6 bypass).tw,ot.
17 (CABG or CAB or ACB).tw,ot.
18 (coronary artery bypass adj6 graft*).tw,ot.
19 (coronary adj6 bypass surg*).tw,ot.
20 or/12-19
21 exp diabetes mellitus/
22 diabet*.tw,ot.
23 (IDDM or NIDDM or MODY or T1DM or T2DM or T1D or T2D).tw,ot.
24 (non insulin* depend* or noninsulin* depend* or non insulin?depend* or noninsulin?depend*).tw,ot.
25 (insulin* depend* or insulin?depend*).tw,ot.
26 or/21-25
27 exp diabetes insipidus/
28 diabet* insipidus.tw,ot.
29 27 or 28
30 26 not 29
31 11 and 20 and 30
32 exp Randomized Controlled Trial/
33 exp Controlled Clinical Trial/
34 exp Clinical Trial/
35 exp Comparative Study/
36 exp Drug comparison/
37 exp Randomization/
38 exp Crossover procedure/
39 exp Double blind procedure/
40 exp Single blind procedure/
41 exp Placebo/
42 exp Prospective Study/
43 ((clinical or control$ or comparativ$ or placebo$ or prospectiv$ or randomi?ed) adj3 (trial$ or stud$)).tw,ot.
44 (random$ adj6 (allocat$ or assign$ or basis or order$)).tw,ot.
45 ((singl$ or doubl$ or trebl$ or tripl$) adj6 (blind$ or mask$)).tw,ot.
46 (cross over or crossover).tw,ot.
47 or/32-46
48 exp meta analysis/
49 (metaanaly$ or meta analy$ or meta?analy$).tw,ot.
50 (search$ adj10 (medical database$ or medline or pubmed or embase or cochrane or cinahl or psycinfo or psyclit or healthstar or biosis or current content$ or systematic$)).tw,ot.
51 exp Literature/
52 exp Biomedical Technology Assessment/
53 hta.tw,ot.
54 (health technology adj6 assessment$).tw,ot.
55 or/48-54
56 47 or 55
57 (comment or editorial or historical-article).pt.
58 56 not 57
59 31 and 58
60 limit 59 to human
'My NCBI' alert service (PubMed)
(percutaneous[All Fields] AND ("heart"[MeSH Terms] OR "heart"[All Fields] OR "coronary"[All Fields])) AND bypass[All Fields] AND ("diabetes mellitus"[MeSH Terms] OR ("diabetes"[All Fields] AND "mellitus"[All Fields]) OR "diabetes mellitus"[All Fields] OR "diabetes"[All Fields]) AND Randomized Controlled Trial[ptyp]

Appendix 2. Description of interventions

CharacteristicPCI
[procedure, type of stent ...]

Adequatea intervention

[Yes/No]

CABG
[surgical approach, graft ... ]

Adequatea comparator

[Yes/No]

Study 1    

"-" denotes not reported

aThe term 'adequate' refers to sufficient use of the intervention/comparator with regard to, for example, provision for contraindications, experience of staff and other features necessary to establish a fair contrast between intervention and comparator

CABG: coronary artery bypass grafting; N: no; PCI: percutaneous coronary intervention; Y: yes

Appendix 3. Baseline characteristics (I)

CharacteristicIntervention(s) and comparator(s)Duration of intervention
(duration of follow-up)
Description of participantsStudy period
[year to year]
CountrySettingEthnic groups
[%]
Duration of diabetes
[mean/range years (SD), or as reported]
Study 1PCI       
 CABG       
      all:  

"-" denotes not reported

CABG: coronary artery bypass grafting; PCI: percutaneous coronary intervention; SD: standard deviation

Appendix 4. Baseline characteristics (II)

CharacteristicIntervention(s) and comparator(s)Duration of multivessel coronary disease
[mean/range years (SD), or as reported]
Sex
[female %]
Age
[mean/range years (SD), or as reported]
HbA1c
[%]
BMI
[mean kg/m² (SD)]
Comedications / CointerventionsComorbidities
Study 1PCI       
 CABG       
 all:       

"-" denotes not reported

BMI: body mass index; CABG: coronary artery bypass grafting; HbA1c: glycosylated hemoglobin A1c; PCI: percutaneous coronary intervention; SD: standard deviation

Appendix 5. Matrix of study endpoints (publications)

Study IDCharacteristic

Endpoint reported

in publication

Endpoint not reported
in publication
Endpoint not
measured
Time of measurementa
Example Review's primary outcomes
All-cause mortalityx  3, 6, 12 mo
Adverse events x N/A
Review's secondary outcomes
Strokex   6, 12 mo
Nonfatal myocardial infarctionx   3, 6, 12 mo
Symptomatic angina x N/A
Repeated revascularization x N/A
Health-related quality of life x N/A
Metabolic control (HbA1c)x  0, 3, 6, 12 mo
Socioeconomic effects x N/A
Other than review's primary/secondary outcomes reported in publication (classification: P/S/O)b
Nocturnal hypoglycemic episodes (O), patient satisfaction (S), safety parameters (O)
Subgroups reported in publication
Age < 65 years vs. ≥ 65 years, type 1 vs. 2 diabetes

aUnderlined data denote times of measurement for primary and secondary review outcomes, if measured and reported in the results section of the publication (other times represent planned but not reported points in time)

b(P) Primary or (S) secondary endpoint(s) refer to verbatim statements in the publication, (O) other endpoints relate to outcomes which were not specified as 'primary' or 'secondary' outcomes in the publication

HbA1c: glycosylated hemoglobin A1c; mo: months; N/A: not applicable

Appendix 6. Matrix of study endpoints (trial documents)

Characteristic / Study ID (trial identifier)Endpointa Review's primary outcome Review's secondary outcomeTime of measurementSource (FDA document/EMA document/manufacturer's website/design paper/trial protocol document)
E x a m p l eAll-cause mortality (P)x 12 mo 
HbA1c (O) x3, 6, 12 mo
Insulin sensitivity (O)N/AN/AN/A
Myocardial infarction (S) x6, 12 mo

"-" denotes not reported

a(P) Primary or (S) secondary endpoint(s) refer to verbatim statements in the publication, (O) other endpoints relate to outcomes which were not specified as 'primary' or 'secondary' outcomes in the report

EMA: European Medicines Agency; FDA: Food and Drug Administration (US); HbA1c: glycosylated hemoglobin A1c; mo: months; N/A: not applicable

Appendix 7. Examination of outcome reporting bias

CharacteristicOutcomeClear that outcome was measured and analyzeda [trial report states that outcome was analyzed but only reports that result was not significant]Clear that outcome was measured and analyzedb [trial report states that outcome was analyzed but no results reported]Clear that outcome was measuredc [clear that outcome was measured but not necessarily analyzed (judgment says likely to have been analyzed but not reported because of nonsignificant results)]Unclear whether the outcome was measuredd [not mentioned but clinical judgment says likely to have been measured and analyzed but not reported on the basis of nonsignificant results]
Study 1     

'High risk of bias' categories for outcome reporting bias according to the Outcome Reporting Bias In Trials (ORBIT) study classification system for missing or incomplete outcome reporting in reports of randomized trials (Kirkham 2010).

aClassification 'A' (table 2, Kirkham 2010)

bClassification 'D' (table 2, Kirkham 2010)

cClassification 'E' (table 2, Kirkham 2010)

dClassification 'G' (table 2, Kirkham 2010)

N/A: not applicable

Appendix 8. Definition of endpoint measurement (I)

CharacteristicHealth-related quality of lifeSocioeconomic effectsStrokeMyocardial infarctionAdverse events: major bleedingAdverse events: renal failureAdverse events: restenosis
Study 1       
N/D: not defined; N/I: not investigated

Appendix 9. Definition of endpoint measurement (II)

Characteristic

Study ID

Symptomatic anginaRepeated revascularizationMild hypoglycemiaModerate hypoglycemiaSevere hypoglycemiaSevere/serious adverse events
Study 1      
N/D: not defined; N/I: not investigated

Appendix 10. Adverse events (I)

CharacteristicIntervention(s) and comparator(s)Participants included in analysis
[N]
Deaths
[N]
Deaths
[%]
All adverse events
[N]
All adverse events
[%]
Severe/serious adverse events
[N]
Severe/serious adverse events
[%]
Study 1PCI       
 CABG       
 all:       

"-" denotes not reported

CABG: coronary artery bypass grafting; PCI: percutaneous coronary intervention

Appendix 11. Adverse events (II)

CharacteristicIntervention(s) and comparator(s)Participants included in analysis
[N]
Discontinued study due to adverse events
[N]
Discontinued study due to adverse events
[%]
Hospitalization
[N]
Hospitalization
[%]
Outpatient treatment
[N]
Outpatient treatment
[%]
Study 1PCI       
 CABG       
 all:       

"-" denotes not reported

CABG: coronary artery bypass grafting; PCI: percutaneous coronary intervention

Appendix 12. Adverse events (III)

CharacteristicIntervention(s) and comparator(s)Participants included in analysis
[N]
All hypoglycemic episodes
[N participants]
All hypoglycemic episodes
[% participants]
Severe/serious hypoglycemic episodes
[N participants]
Severe/serious hypoglycemic episodes
[% participants]
Study 1PCI     
 CABG     
 all:     

"-" denotes not reported

CABG: coronary artery bypass grafting; PCI: percutaneous coronary intervention

Appendix 13. Adverse events (IV)

CharacteristicIntervention(s) and comparator(s)Participants included in analysis
[N]
Specific adverse events
[description]
Specific adverse events
[N participants]
Specific adverse events
[% participants]
Study 1PCI 

1. Major bleeding

2. Renal failure

3. Restenosis

1.

2.

3.

1.

2.

3.

CABG 

1. Major bleeding

2. Renal failure

3. Restenosis

1.

2.

3.

1.

2.

3.

all:

1. Major bleeding

2. Renal failure

3. Restenosis

1.

2.

3.

1.

2.

3.

"-" denotes not reported

CABG: coronary artery bypass grafting; PCI: percutaneous coronary intervention

Appendix 14. Survey of authors providing information on included trials

CharacteristicStudy author contacted
[DD/MM/YY]
Study author replied
[DD/MM/YY]
Study author asked for additional information
[DD/MM/YY: short summary]
Study author provided data
[DD/MM/YY: short summary]
Study 1Yes, date:Yes, date: ... / NoDate: ...Date: ...
N/A: not applicable

Contributions of authors

Claudio Bravo (CB): protocol draft, search strategy development, trial selection, data extraction, data analysis, data interpretation, review draft, and future review updates.

Carlos M Rondon Clavo (CR): trial selection, data extraction, and review draft.

Patricio Oliva (PO): acquiring trial reports, data analysis, data interpretation, and review draft.

Gabriel Rada (GR): protocol draft, data analysis, data interpretation, and review draft.

Marcela Rivera-Cornejo (MRC): search strategy development, acquiring trial reports, and review draft.

Romina Torres-Robles (RTR): search strategy development, acquiring trial reports, and review draft.

Declarations of interest

CB: none known.

CR: none known.

PO: none known.

GR: none known.

MRC: none known.

RTR: none known.

Ancillary